DCC-2618,apan-KITandPDGFRAswitchcontrolinhibitor,achievesproof-of-concept

inafirst-in-humanstudy

FilipJanku,SuzanneGeorge,AlbiRazak,MichaelGordon,DavidBrooks,DanielFlynn,MichaelKaufman,JamaPitman,BryanSmith,Neeta

Somaiah,EricGerstenberger,DebWestwood,OliverRosen

2016 EORTC-NCI-AACRDecember 1, 2016

DISCLOSURES

• F.Janku:ResearchfundingfromDeciphera,SABDeciphera• S.George:ResearchfundingfromDeciphera,Blueprint

Medicine,Pfizer,Bayer,Novartis• A.Razak:ResearchfundingfromDeciphera• M.Gordon:ResearchfundingfromDeciphera• D.G.Brooks,D.Flynn,M.Kaufman,J.Pitman,O.Rosen,B.

Smith,D.Westwood:Deciphera employees

• Ongoingstudy:Presentationcontainspreliminarydatathatarepartiallymonitoredandvalidated

BACKGROUND

• DCC-2618isaKIT andPDGFRAinhibitorresilienttogain-of-functionanddrugresistancemutationsmutations– PotencyindependentofATP

concentration

• DCC-2618wasdesignedtopotentlyinhibitabroadrangeofmutationsinKIT andPDGFRA kinases

• Gastrointestinalstromaltumor(GIST)isanimportantdiseasetoachieveproof-of-conceptintheFIHstudyduetothemultiplicityandheterogeneityofresistancemutationswithinKIT

Deciphera’s Switch Control Inhibition

RATIONALEFORDCC-2618STUDY• ActivityregardlesswhetherprimarymutationisinKIT Exon9,Exon11,orExon17

– IC50 forKIT Exon11deletion3nM,IC50PDGFRA D842V60nM• BroadactivityinsecondaryKITmutationsacrossExons13,14,17,and18

– ActivemetaboliteDP-5439possessescomparableactivityacrossallmutations• KIT T670IandV654AsecondarymutationsaretheleastsensitivetoDCC-2618

– IC50 forKIT T670I221nM ,IC50 for189nM forKITV654A

D81

6VD

820A

DV

559-

V56

0/D

816V

AY

du

p/N

655S

AY

du

p/N

680K

AY

du

p/D

816G

AY

du

p/D

820G

AY

du

p/D

820E

AY

du

p/N

822K

AY

du

p/N

822Y

AY

du

p/N

822H

WK

V55

7C/T

670I

WK

V55

7C/D

820Y

WK

V55

7CD

820A

V56

0D/V

654A

V56

0D/T

670I

V56

0D/N

822K

V56

0D/Y

823D

D81

6VD

820A

DV

559-

V56

0/D

816V

AY

du

p/N

655S

AY

du

p/N

680K

AY

du

p/D

816G

AY

du

p/D

820G

AY

du

p/D

820E

AY

du

p/N

822K

AY

du

p/N

822Y

AY

du

p/N

822H

WK

V55

7C/T

670I

WK

V55

7C/D

820Y

WK

V55

7CD

820A

V56

0D/V

654A

V56

0D/T

670I

V56

0D/N

822K

V56

0D/Y

823D

D81

6VD

820A

DV

559-

V56

0/D

816V

AY

du

p/N

655S

AY

du

p/N

680K

AY

du

p/D

816G

AY

du

p/D

820G

AY

du

p/D

820E

AY

du

p/N

822K

AY

du

p/N

822Y

AY

du

p/N

822H

WK

V55

7C/T

670I

WK

V55

7C/D

820Y

WK

V55

7CD

820A

V56

0D/V

654A

V56

0D/T

670I

V56

0D/N

822K

V56

0D/Y

823D

D81

6VD

820A

DV

559-

V56

0/D

816V

AY

du

p/N

655S

AY

du

p/N

680K

AY

du

p/D

816G

AY

du

p/D

820G

AY

du

p/D

820E

AY

du

p/N

822K

AY

du

p/N

822Y

AY

du

p/N

822H

WK

V55

7C/T

670I

WK

V55

7C/D

820Y

WK

V55

7CD

820A

V56

0D/V

654A

V56

0D/T

670I

V56

0D/N

822K

V56

0D/Y

823D

0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

C H O K IT M u ta n t A s s a y s

IC5

0 (

nM

)

ND

ND

D C C -2 6 1 8 Im a tin ib S u n it in ib R e g o ra fe n ib

DCC-2618-01-001:DESIGNANDOBJECTIVES• Design(NCT02571036)

– Pharmacologically-guided3+3escalationphaseIstudyoforalDCC-2618administeredBIDevery28days

• Objectives– Primary:Safety,tolerability,maximumtolerateddose(MTD),dose-

limitingtoxicities(DLT)– Secondary:Pharmacokineticprofile,antitumorefficacy– Exploratory:DeterminationofKIT and/orPDGFRAmutationsinplasma

cell-freeDNA(NGS)andserumtryptase

• Majoreligibilitycriteria– Patientswithadvancedrefractorycancersandmolecularrationalefor

activity– ECOG0-1– Adequateorganfunction– PriorKIT/PDGFRAinhibitorswereallowed

DCC-2618:DOSELEVELS&PATIENTSCHARACTERISTICS

DoseLevel(mg)(TimeonStudy)

NumberofPatients TumorTypes: Tissueand/orPlasma cfDNA Mutations

20BID(1x> 1year) 4 GIST:KIT Exon11(1x),KIT Exon17(1x),PDGFRA (1x)

GBM:PDGFRA/KIT/KDR co-amplified(1x)

30BID(1x6 months*) 4

GIST:KIT Exon11(1x),KITExon11 &17(1x)Thymic Carcinoma:KIT Exon11(1x)Desmoid tumor(1x)

50BID(2x> 6 months) 4 GIST:KIT Exon9(1x),KITExon11(3x)

100BID 6 GIST: KIT Exon9(x3),KITExon11(1x),PDGFRA Exon18(1x),SDHA(1x)

150BID 6 GIST: KIT Exon9(x2),KITExon11(x3),KITExon17(1x)

200BID Enrolling

Enrolled: 24 patients with mean of 4.7 prior therapies

*Patient stayed on study following PD due to clinical benefit

1Grade 3 Lipase Elevation (asymptomatic) was a DLT in 100 mg BID Cohort2150 mg BID Cohort330 mg BID Cohort (event considered likely to be exercise-induced)

AdverseEvent Total G1/2 G3/4 AdverseEvent Total G1/2 G3/4Fatigue 10 9 1 BloodCPKincrease 3 2 13Anaemia 9 4 5 Hyperglycemia 3 3 0Lipaseincreased 8 6 21 Hypoalbuminaemia 3 3 0Dyspnoea 7 7 0 Dizziness 3 3 0Abdominalpain 6 5 1 Cough 3 3 0Decreasedappetite 6 6 0 Rash 3 3 0Amylaseincreased 6 6 0 Hotflush 3 3 0Vomiting 5 5 0 Thrombocytopenia 2 2 0Myalgia 5 5 0 Hypothyroidism 2 2 0Alopecia 5 5 0 Drymouth 2 2 0Diarrhoea 4 4 0 Hypoalbuminemia 2 2 0Weightdecreased 4 4 0 ASTincreased 2 2 0Hypokalemia 4 3 1 Bilirubinincreased 2 2 0Arthralgia 4 4 0 Hypomagnesaemia 2 2 0Handfootsyndrome 4 3 0 Hypophosphataemia 2 1 1Hypertension 4 3 12 MuscleSpasms 2 2 0Constipation 3 3 0 Headache 2 2 0Nausea 3 3 0 Anxiety 2 2 0Edemaperipheral 3 3 0 Insomnia 2 2 0Pyrexia 3 3 0 Dryskin 2 2 0Increased alk.phosphatase 3 3 0 Melena 2 1 1

TREATMENTEMERGENTADVERSEEVENTS(N=24,cut-off4NOV2016)

DCC-2618* Cycle1Pharmacokinetics:150mgBIDCohortandAcrossAllDosingCohorts

*combined plasma concentration of DCC-2618 and its active metabolite DP-5439

T670I IC90 level: 1016 ng/ml (1989 nM ) achieved at Cmin of 50 mg BID

DAY 15

DAY -7, DAY 1, DAY 15

DCC-2618:CYCLE1PETINGISTPATIENTSDoseLevelmgBID

MutantGene

PatientID

InvestigatorReview

CTScanC3D1

30 KIT 01.001 PMR SD50 KIT 01.003 PMR PD50 KIT 03.003 PMR SD50 KIT 03.004 PMR SD50 KIT 04.008 PMR SD100 KIT 04.009 PMR PR100 KIT 01.004 PMR SD100 KIT 04.010 PMR SD100 KIT 01.005 PMR SD150 KIT 01.007 PMR SD150 KIT 02.002 PMR SD150 KIT 03.005 PMR SD150 KIT 01.006 PMR PD150 KIT 04.012 PMR Tooearly150 KIT 03.007 PMD SD100 PDGFRA 04.011 SMD SD100 SDHA 03.006 SMD PD

Baseline Cycle1

• 14 of 15 patients with KIT-mutant GIST had PMR

• 13 of 15 patients with KIT-mutant GIST had PMRconfirmed by central review, using EORTC PET response criteria

DCC-2618:RECISTRESPONSES

MRIaftercycle12

CTaftercycle2BaselineCT

BaselineMRI

§ Widely metastatic GIST with KIT Exon 11 deletion, who received 6 different prior KIT inhibitors

§ RECIST: partial response (-37%) maintained for 5+ cycles on DL4 100mg BID

§ Glioblastoma multiformewith PDGFRA / KIT / KDR co-amplification, who received prior XRT and temozolomide and progressed after 3 months

§ RECIST: partial response (-49%), on study for 12+ cycles on DL1 20mg BID

§ RANO: PR after cycle 12

SUMMARYOFEFFICACY(n=24)

• RECIST– PRinheavilypretreatedpatientwithGISTKITexon11/17mutation– PRinpretreatedpatientwithGBMwithPDGFRA/KIT/KDR co-

amplification(confirmedbyRANO)

• PETmetabolicresponses– PMRin14of15patientswithheavilypretreatedGISTandKIT

mutation(s),13oftheseresponseshavebeenconfirmedbycentralreview(analysisongoing)

• Timeontherapy– ApatientwithGBMwithPDGFRA/KIT/KDR co-amplificationon

therapyfor12+months– ThreepatientswithheavilypretreatedGISTontherapyfor> 6months

DCC-2618:PLASMAcfDNA KITMUTATIONS

Patient(dosemg)

No.ofKITmutations

ChangeinKITmutationallelefraction(MAF) Comment

1(30BID) 2 UndetectableafterC2- C6 IncludesExon17(N822K)resistance

mutation

2(50BID) 1 UndetectableafterC2&C4 Exon11initiating mutation

3(50 BID) 6 Allmutations undetectable

afterC2Includes 3distinctExon17resistancemutations(D816E,D820Y,andY823D)

4(50BID) 2 MAF16 &21x↓afterC2 IncludesExon14(N680K)resistance

mutation

5(50BID) 3 MAF50to >600x↓afterC2;

136to>600x↓afterC4

Resistance mutationsinExons13(V654A)&Exon18(A829P)undetectableafterC2&4

6(100BID) 1 UndetectableafterC2 Exon9initiating duplication

7(100BID) 3 MAF9-10x↓afterC2 Includes knownExon13(K642E)and

Exon17(N822K)resistancemutations

In 13/15 patients, we detected total of 33 KIT mutations in 6 exons (9, 11, 13, 14, 17, 18)

DCC-2618:DOSERESPONSERELATIONSHIPWITHSERUMTRYPTASELEVELS

Limit of detection(LabCorp)

Cohort (mg BID) Pre-treatmentMean± SD OntreatmentMean± SD P-value

20 3.57± 1.05 2.55± 1.04 0.073

30 3.08± 0.97 1.82± 0.95 0.011

50 2.48± 0.35 1.15± 0.33 <.001

100 2.27± 0.47 0.76± 0.44 <.001

150 3.24± 0.49 0.72± 0.47 <.001

P < 0.05 for tryptase decline as a function of dose

• DCC-2618iswelltoleratedtodatewithanencouragingsafetyprofileandrobustexposurefollowingoraldosesfrom20to150mgBID−Startingat50mgBID,meantroughlevelsofcombinedplasmaconcentrationexceedIC90 ofleastsensitivemutations T670IandV654A

−MTDhasnotbeenreachedyetanddoseescalationisongoing−Asymptomaticgrade3lipaseelevationhasbeentheonlyDLTtodate

• PreliminarysignalsofactivityperRECISTandPEThavebeenobservedinpretreatedpatientGBMwithco-amplificationofPDGFRA/KIT/KDRandGIST(s)with KITmutations

• DCC-2618leadstorapidclearanceofbroadspectrumofKITmutationsfromplasmacfDNA inpatientswithheavilypretreatedGIST

• Dose-dependentrapidreductionofserumtryptase warrantstestingofDCC-2618insystemicmastocytosis

CONCLUSIONS

ACKNOWLEDGEMENTSMDAndersonCancerCenter• NeetaSomaiah,MD• Vivek Subbiah,MD• SarinaPiha-Paul,MD• Funda Meric-Bernstam,MD• AungNaing,MD• Shubham Pant,MD• ChenGuo,PhD• JohndeGroot,MD• Nishma M.Ramzanali• Divya Sakamuri,MD• VandaStepanek,MD,PhD

DanaFarberCancerInstitute• SuzanneGeorge,MD• MicheleDorio,RN• MelissaHohos,RN• JuliaJ.Jennings• SarahSolomon• StephanieN.Vangellow

PrincessMargaretCancerCenter• Albiruni Razak,MD• Samer Salah• PenelopeBradbury• MaraKolodziejczyk,RN,MScN• MaryamMasood

HonorHealthResearchInstitute• MichaelGordon,MD• KristinHendrickson,BA,RN• AgnieszkaJezierska-Drutel• LeticiaLebron,RN,BSN

GuardantHealth• ElenaHelman

Nuventra• GrantHogeland,PharmD• DavidMitchell,PhD

Deciphera• Dennise Greensmith• DanLarson• LindaMartin• NicoleTurcuotte

OUR PATIENTS AND THEIR FAMILIES